DESCRIPTION: This proposal is targeted at elucidating the signaling mechanisms of the insulin-like growth factor-1 (IGF-I) receptor that are responsible for its unique anti-apoptotic effects. Previous studies have shown that IGF-I is one of very few survival factors that exhibit anti-apoptotic effects, although relatively little is known about the regulatory events that are associated with this aspect of IGF-I action. In this regard, the applicant has identified two anti-apoptotic pathways that are influenced by the IGF-I receptor. First, at low IGF-I receptor levels, the ability of IGF-I to protect against UV-induced apoptosis is attenuated by low concentrations of wortmannin, thereby suggesting phosphatidylinositol 3-kinase (PI 3-kinase) involvement. Secondly, when the IGF-I receptor is over-expressed in fibroblasts, the protective effect is insensitive to even very high levels of wortmannin. The applicant indicates that it is important to understand the signaling pathways associated with each event, i.e., the wortmannin- sensitive pathway should be studied because it represents a key and novel function of a tyrosine kinase receptor, whereas the wortmannin-insensitive pathway should also be examined because it may reflect the anti-apoptotic mechanisms used by transformed cells that often over-express growth factor receptors. In addition, the investigator has found that over-expression of a kinase-defective IGF-I receptor further sensitizes the cells to apoptosis, perhaps by sequestering a signaling molecule that is necessary to inhibit apoptosis. Therefore, the Specific Aims of the proposal are: 1) Characterize the apoptosis-related regulatory properties of the IGF-I receptor and its partners. These studies will be directed towards identifying the receptor domains that affect apoptosis and the role of adaptor proteins in this process. 2) Analyze the downstream proteins and events in the anti-apoptotic pathway initiated by the IGF-I receptor. These investigations will assess a) the role of PI 3-kinase b) the regulation of stress kinases, c) the participation of the bcl-2 family in IGF-I receptor signaling, and d) the role of a newly identified MEK activator.